Effects of prenatal exposures to maternal obesity and gestational diabetes on metabolic decline from childhood to adolescence and underlying neurobiological pathways

产前暴露于母亲肥胖和妊娠糖尿病对儿童期至青春期代谢下降和潜在神经生物学途径的影响

• 批准号: 10682336
• 负责人: Kathleen Alanna Page
• 金额: $ 72.76万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-28 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682336
• 关键词: Adolescence; Adolescent; Age; Animal Model; Animals; Behavior; Beta Cell; Biological; Body mass index; Brain; Brain Mapping; Caring; Cell physiology; Child; Childhood; Coupled; Cross-Sectional Studies; Data; Desire for food; Development; Diabetes Mellitus; Diet; Eating; Energy Intake; Event; Evolution; Exposure to; Food; Functional disorder; Future; Future Generations; Gestational Diabetes; Glucose; Hippocampus; Human; Hypothalamic structure; Impairment; Insulin Resistance; Intervention; Knowledge; Lead; Life; Life Style; Link; Longitudinal Studies; Measures; Mediating; Mediation; Metabolic; Methods; Modeling; Modification; Mothers; Neurobiology; Neurosecretory Systems; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Obesity; Outcome; Pathogenesis; Pathway interactions; Personal Satisfaction; Phenotype; Physical activity; Predisposition; Pregnancy Complications; Prevalence; Puberty; Public Health; Regulation; Rewards; Risk; Risk Reduction; Rodent Model; Sampling; Satiation; Signal Transduction; Sleep; System; Testing; Time; Weight Gain; Work; Youth; biomarker identification; brain pathway; brain reward regions; cohort; critical developmental period; cue reactivity; diabetes risk; energy balance; fetal programming; follow-up; global health; human study; insulin secretion; insulin sensitivity; knowledge base; maternal diabetes; maternal obesity; metabolic phenotype; neural; neurodevelopment; neuroimaging; obesity development; obesity in children; obesity in pregnancy; obesity risk; offspring; postnatal; prenatal exposure; prepregnancy; recruit; response; transmission process; trend; type 2 diabetes in children

PROJECT SUMMARY/ABSTRACT Rising childhood obesity rates are coupled with an alarming increase in the prevalence of type 2 diabetes in children and adolescents. Evidence suggests that in utero exposures to maternal obesity and/or gestational diabetes mellitus (GDM) contribute to these upward trends, and the effects of these prenatal exposures on metabolic risk become more pronounced during adolescence. While the biological mechanisms of such maternal-fetal programming are poorly understood, compelling studies in rodent models show that in utero exposure to maternal obesity and/or diabetes causes abnormal development of brain pathways involved in energy balance regulation, leading to obesity and type 2 diabetes later in life. Our group was the first to study the effects in utero exposures to maternal obesity and GDM on brain pathways and metabolic outcomes in humans using a pioneering approach combining neuroimaging methods and metabolic phenotyping in children. To date, findings from cross-sectional studies in our BrainChild cohort provide strong support for the neuroendocrine programming effects seen in animal models. The earliest abnormality we have identified involves modification of brain pathways known to be involved in energy balance regulation. These brain modifications were predictive of increases in food intake and weight gain in children during short term follow-up and lead to the primary hypothesis of the present study: that differences in the neural markers observed in children at age 7-10 will be predictive of metabolic outcomes during the transition to adolescence, a critical time for brain development and metabolic decline. Child postnatal behaviors including physical activity, diet and sleep may also be mediating or modifying the effects of brain pathways linking in utero exposures to maternal GDM and obesity on child metabolic trajectories. We will include measures of these behaviors and explore these pathways to generate important data for future studies focusing on lifestyle behaviors. The proposed longitudinal study of the BrainChild cohort for up to six years of follow up provides the unique opportunity to advance our understanding of the interplay among brain changes, obesity, insulin resistance and beta cell function at early stages in the evolution of transgenerational transmission of obesity and diabetes risks. Given the growing number of pregnancies complicated by maternal obesity and GDM, the well-being of future generations may depend to an important degree on developing interventions that can break the vicious transgenerational cycle of obesity and diabetes. The proposed studies will contribute critical information to the knowledge base required for development of such interventions.

项目总结/摘要 儿童肥胖率的上升伴随着2型糖尿病患病率的惊人增加， 儿童和青少年。有证据表明，在子宫内暴露于母体肥胖和/或妊娠 糖尿病（GDM）有助于这些上升趋势，这些产前暴露的影响， 代谢风险在青春期变得更加明显。虽然这种生物学机制 母胎编程知之甚少，在啮齿动物模型中令人信服的研究表明，在子宫内， 暴露于母体肥胖和/或糖尿病会导致参与以下过程的脑通路的异常发育： 能量平衡调节，导致肥胖和2型糖尿病在以后的生活。 我们的小组是第一个研究子宫内暴露于母体肥胖和GDM对大脑通路的影响的小组 和代谢结果在人类中使用一种开创性的方法结合神经成像方法， 儿童代谢表型。迄今为止，我们的BrainChild队列的横断面研究结果 为在动物模型中观察到的神经内分泌编程效应提供了强有力的支持。最早的 我们发现的异常涉及已知参与能量平衡的大脑通路的改变 调控这些大脑的变化预示着儿童的食物摄入量和体重增加 并导致本研究的主要假设： 在7-10岁儿童中观察到的神经标记物将预测过渡期间的代谢结果 到青春期，大脑发育和代谢下降的关键时期。儿童产后行为包括 身体活动、饮食和睡眠也可能调节或改变大脑通路的影响， 母体妊娠期糖尿病和肥胖对儿童代谢轨迹的影响。我们将采取措施， 这些行为，并探索这些途径，以产生重要的数据，为未来的研究，重点是生活方式 行为。 拟议的BrainChild队列长达6年的纵向研究提供了独特的 有机会增进我们对大脑变化、肥胖、胰岛素抵抗和 在肥胖和糖尿病的跨代传播的演变的早期阶段的β细胞功能 风险鉴于越来越多的怀孕并发孕妇肥胖和GDM， 未来几代人可能在很大程度上依赖于制定干预措施， 肥胖和糖尿病的代际循环。拟议的研究将提供关键信息， 制定此类干预措施所需的知识基础。